(Poly) aminoacetamide derivatives of epipodophyllotoxin their process of preparation and their applications in therapeutics as anticancer agents

Abstract

The present invention relates to novel podophyllotoxin derivatives substituted in the 4-position by a substituted (poly)aminoalkylaminoacetamide chain, to their process of preparation and to their use as medicament as anticancer agents.

The invention claimed is:   
     
       1. A method of treating non-solid tumours and/or solid tumours selected from the group consisting of melanoma, lung, breast, ovarian and leukaemia, which comprises administering to a patient in need thereof an effective amount of a compound or a pharmaceutically acceptable salt of formula (I) 
       
         
           
           
               
               
           
         
       
       in which
 R 1  and R 2  represent, independently of one another, a hydrogen atom or a methyl radical; 
 R3 and A together form a C 3 -C 8  saturated aliphatic ring, comprising one or more heteroatoms 
 
       or
 R3 represents a radical chosen from the group consisting of a hydrogen atom, a C 1 -C 4  alkyl radical and a benzyl radical and A represents a radical chosen from the group consisting of a hydrogen atom, a C 1 -C 4  alkyl radical, a benzyl radical and a group of formula (II) 
 
       
         
           
           
               
               
           
         
       
       in which
 a varies from 2 to 5, 
 R4 and B together form a C 3 -C 8  ring 
 or 
 R4 represents a radical chosen from the group consisting of a hydrogen atom, a C 1 -C 4  alkyl radical and a benzyl radical, it being possible for R3 and R4 to be connected by an alkylene chain comprising 2 or 3 carbon atoms, and B represents a radical chosen from the group consisting of: 
 a hydrogen atom, 
 a C 1 -C 4  alkyl radical, 
 a benzyl radical, 
 a group of formula (III) 
 
       
         
           
           
               
               
           
         
       
       in which b and c can vary, independently of one another, from 2 to 5 and R5 to R7 represent, independently of one another, a radical chosen from the group consisting of a hydrogen atom, a C 1 -C 4  alkyl radical and a benzyl radical, it being possible for R4 and R5 and/or R5 and R6 and/or R6 and R7 to be connected by an alkylene chain comprising 2 or 3 carbon atoms;
 and a group of formula (IV) 
 
       
         
           
           
               
               
           
         
         in which c can vary from 2 to 5 and R8 and R9 represent, each independently of one another, a hydrogen atom or a C 1 -C 5  alkyl radical, it being possible for R4 and R8 to be connected by an alkylene chain comprising 2 or 3 carbon atoms, or R8 and R9 together form a C 3 -C 8  ring; or their pharmaceutically acceptable salts, in particular their addition salts, with inorganic or organic acids. 
       
     
     
       2. The method according to  claim 1  which further comprises administering an anticancer agent, wherein the administrating is simultaneous, separate or spread out over time. 
     
     
       3. The method according to  claim 2 , wherein the anticancer agent is chosen from the group consisting of platinum derivatives, taxanes, vincas and 5-FU. 
     
     
       4. The method according to  claim 1 , wherein said non-solid tumours and/or solid tumours are resistant to conventional therapies. 
     
     
       5. The method according to  claim 1 , wherein the leukaemia is lymphoma or myeloma.